PROJECT SUMMARY A major hurdle to compliance with rehabilitation therapies is poor effort on the part of patients, caused by fatigue and feelings of insurmountable effort. If a physical exercise feels very effortful one may be unwilling to exert the effort required, whereas if an exercise feels less effortful one may be more likely to persevere. Despite the ubiquity of effort-based judgments, and their disruption in a variety of neurological conditions, the mechanisms responsible for the subjective valuation of physical effort have received limited investigation. The central hypothesis of this proposal is that an individual's subjective valuation of effort is reflected in her inherent excitability of motor cortex, and that this metric is sensitive to disease state. We will perform experiments in healthy human participants; and a group of participants with multiple sclerosis (MS). We have developed a novel effort-based choice paradigm that allows us to obtain a precise objective measure of an individual's subjective valuation of effort. We will use this approach, in combination with computational modeling, functional magnetic resonance imaging (fMRI), and noninvasive brain stimulation, to investigate the mechanisms responsible for the subjective valuation of effort. In Aim 1 we will study how motor physiology influences subjective effort valuation in healthy participants. We will use transcranial magnetic stimulation (TMS) to non invasively probe the physiological properties of participants' motor cortex; and we will have the same participants make decisions about effort while they are scanned with fMRI, and use this data to computationally model their subjective valuation of effort and associated brain activity. These experiments will allow us to test the relationships between an individual's representations of effort value and motor physiology. In Aim 2 we will identify the mechanisms of subjective effort valuation in patients with MS. We will use TMS and fMRI to investigate the neural and behavioral representations of effort value in MS. These experiments will shed light on the neural circuits that are disrupted in individuals with MS, suffering from feelings of fatigue. Our studies will have a broad impact on the fields of decision-making and motor control by dissecting the fundamental mechanisms responsible for physical effort valuation. This work will provide an understanding of the neural mechanisms underlying disrupted feelings of effort in MS, and may eventually reveal neurobehavioral markers and neuromodulatory interventions to aid in the prediction and treatment of rehabilitation non-compliance.